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Single neonatal dexamethasone administration has long-lasting outcome on depressive-like behaviour, Bdnf, Nt-3,
D A Lanshakov1, E V Sukhareva2,3, V V Bulygina2
1Laboratory of Postgenomics Neurobiology, Institute of Cytology and Genetics, Russian Academy of Science, Novosibirsk, Russian Federation, 630090. lanshakov@bionet.nsc.ru.
Insights
Neonatal dexamethasone exposure alters neurotrophin and receptor expression in rat pups, impacting later-life behavior and stress responses. This research sheds light on the molecular mechanisms behind glucocorticoid programming effects on the developing brain.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Antenatal glucocorticoid exposure, often from preterm birth treatment, can cause long-term neurodevelopmental and behavioral issues.
- The precise molecular pathways through which early-life glucocorticoids program behavior remain unclear.
- The hippocampus and brainstem are critical regions implicated in psychopathologies.
Purpose of the Study:
- To investigate the molecular mechanisms of antenatal glucocorticoid programming on behavior.
- To examine changes in neurotrophin and receptor expression following early postnatal dexamethasone administration.
- To assess the combined effects of neonatal dexamethasone and adolescent stress on depressive-like behaviors.
Main Methods:
- Subcutaneous injection of dexamethasone (DEX) to P2 rat pups.
- Quantification of neurotrophin (Bdnf, Nt-3, Ngf) and receptor (p75ngfr, Sorcs3) expression in the hippocampus (HPC).
- Immunohistochemical analysis of P75NTR protein in brainstem norepinephrine (NE) neurons and assessment of depressive-like behavior.
Main Results:
- Dexamethasone increased neurotrophin expression in the HPC and decreased receptor expression in brainstem NE neurons within hours.
- Neonatal DEX exposure reduced depressive-like behavior independently of chronic stress.
- Neonatal DEX decreased Ntf3 and SorCS1 expression in the brainstem, and blunted the decrease in Bdnf mRNA after stress.
Conclusions:
- Early postnatal dexamethasone exposure induces significant, rapid changes in neurotrophin signaling pathways.
- Neonatal glucocorticoid programming can mitigate depressive-like behaviors, but alters stress-related gene expression.
- Adolescent stress further modifies brainstem receptor expression in DEX-exposed animals, suggesting complex long-term programming effects.
Abstract:
Elevated glucocorticoid level in the early postnatal period is associated with glucocorticoid therapy prescribed at preterm delivery most often has severe long-lasting neurodevelopmental and behavioural effects. Detailed molecular mechanisms of such programming action of antenatal glucocorticoids on behaviour are still poorly understood. To address this question we studied neurotrophins: Bdnf, Nt-3, Ngf and their receptors: p75ngfr, Sorcs3 expression changes after subcutaneous dexamethasone (DEX) 0.2 mg/kg injection to P2 rat pups. Neurotrophins expression level was studied in the hippocampus (HPC). Disturbances in these brain regions have been implicated in the emergence of multiple psychopathologies. p75ngfr and Sorcs3 expression was studied in the brainstem-region where monoamine neurons are located. Immunohistochemically P75NTR protein level changes after DEX were investigated in the brainstem Locus Coereleus norepinephrine neurons (NE). In the first hours after DEX administration elevation of neurotrophins expression in HPC and decline of receptor's expression in the NE brainstem neurons were observed. Another critical time point during maturation is adolescence. Impact of elevated glucocorticoid level in the neonatal period and unpredictable stress (CMUS) at the end of adolescence on depressive-like behaviour was studied. Single neonatal DEX injection leads to decrease in depressive-like behaviour, observed in FST, independently from chronic stress. Neonatal DEX administration decreased Ntf3 and SorCS1 expression in the brainstem. Also Bdnf mRNA level in the brainstem of these animals didn't decrease after FST. CMUS at the end of adolescence changed p75ngfr and SorCS3 expression in the brainstem in the animals that received single neonatal DEX administration.
